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Pre‐ and postnatal growth failure with microcephaly due to two novel heterozygous IGF1R mutations and response to growth hormone treatment
Author(s) -
Gkourogianni Alexandra,
Andrade Anenisia C.,
Jonsson BjörnAnders,
Segerlund Emma,
WernerSperker Antje,
Horemuzova Eva,
Dahlgren Jovanna,
Burstedt Magnus,
Nilsson Ola
Publication year - 2020
Publication title -
acta paediatrica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.772
H-Index - 115
eISSN - 1651-2227
pISSN - 0803-5253
DOI - 10.1111/apa.15218
Subject(s) - microcephaly , proband , short stature , insulin like growth factor 1 receptor , dwarfism , missense mutation , medicine , endocrinology , mutation , compound heterozygosity , genetic heterogeneity , genetics , phenotype , sanger sequencing , biology , gene , pediatrics , growth factor , receptor
Aim To explore the phenotype and response to growth hormone in patients with heterozygous mutations in the insulin‐like growth factor I receptor gene ( IGF1R ). Methods Children with short stature, microcephaly, born SGA combined with biochemical sign of IGF‐I insensitivity were analysed for IGF1R mutations or deletions using Sanger sequencing and Multiple ligation‐dependent probe amplification analysis. Results In two families, a novel heterozygous non‐synonymous missense IGF1R variant was identified. In family 1, c.3364G > T, p.(Gly1122Cys) was found in the proband and co‐segregated perfectly with the phenotype in three generations. In family 2, a de novo variant c.3530G > A, p.(Arg1177His) was detected. Both variants were rare, not present in the GnomAD database. Three individuals carrying IGF1R mutations have received rhGH treatment. The average gain in height SDS during treatment was 0.42 (range: 0.26‐0.60) and 0.64 (range: 0.32‐0.86) after 1 and 2 years of treatment, respectively. Conclusion Our study presents two heterozygous IGF1R mutations causing pre‐ and postnatal growth failure and microcephaly and also indicates that individuals with heterozygous IGF1R mutations can respond to rhGH treatment. The findings highlight that sequencing of the IGF1R should be considered in children with microcephaly and short stature due to pre‐ and postnatal growth failure.